Lansoprazole of the following formula (1)
exhibits potent antibacterial activity, and is broadly used for treating gastric ulcer.
Lansoprazole is a proton pump inhibitor (PPI), and sweeps over the gastric ulcer market of the whole world, along with Omeprazole. H. pylori, one of the bacteria causing gastric ulcer, is completely controlled when Lansoprazole is administered together with Clarithromycin, and so Lansoprazole is very effective for the prevention of relapse as well as treatment of ulcer, and has excellent selectivity.
As the crystalline forms of Lansoprazole, Form A and Form B have been known [Farm vesin 1997, 48, 242-243, 290-291 (The Second Central European Symposium on Pharmaceutical Technology)]. As a matter of terminology, PCT/PL00/00042 (Instytut Farmacetutyczny) uses Form I and Form II, which are different from Form A and Form B, but have substantially same concepts as Form A and Form B. Further, US2004/0010151 (Nina Finkelstein, Shomit Wizel) [Lansoprazole Polymorphs and processes for preparation thereof] describes three forms of Lansoprazole: Form D, Form E, and Form F.
Crystalline Form A of Lansoprazole is used for the marketing agent, and is thermodynamically more stable than the Form B. That is, Form A has such high stability that it does not change even when stored for one year at room temperature or elevated temperature. On the other hand, Form B shows high stability when stored for one year at a low temperature (0° C. or lower), but shows some change in the crystalline form at elevated temperature. Thus, though Crystalline Form B of Lansoprazole has excellent solubility, Form A is used as medicine. In case of Forms D, F and F, the wet state (Form D) has a different form from the dry state (Form E). Conventionally, the crystalline form of Lansoprazole is obtained as a mixture of Forms A and D. Also, the crystalline form can be converted only through special processes that are industrially difficult to apply, such as applying mortar to convert the crystalline forms.
Many reports have been published for the preparing process of Crystalline Form B of Lansoprazole and for the conversion of Form B to Form A [PCT/PL00/00042; Farm vesin 1997, 48, 242-243, 290-291; and KR0433735 (C-Tri)]. The art-known processes for preparing Crystalline Form A of Lansoprazole may be summarized as follows:
[The First Process]
The method reported in Farm vesin shows that the conversion of Form B to Form A may occur according to the changes of temperature and mechanical stress. For example, the correlation between temperature and crystalline form conversion shows that Form B is slowly converted to Form A at a temperature of 10° C. or lower, but rapidly at 40° C. Further, the crystalline form conversion may be facilitated, as the mechanical stress on the Crystalline Form B of Lansoprazole changes. As the example, it is shown that the velocity of force during grinding or compression is correlated with the degree of crystalline form conversion.
However, in this method, the form of Lansoprazole present at the contact portion during grinding or compression may be converted, but that of Lansoprazole at the other portion does not change, and so pure Crystalline Form A of Lansoprazole is difficult to obtain. Therefore, to obtain pure Form A, the same process should be repeated, which requires a long operation time and also may cause polymorphism according to the conversion degrees of crystalline forms.
[The Second Process]
This method is reported in PCT/PL00/00042; and first prepares Form B and converts it to Form A. This method may be briefly summarized as follows.
Crude Lansoprazole prepared from the starting material 2-([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl)thio-1H-benzimidazole is added to 90% ethanol, dissolved by heating to 55° C., filtered, and cooled to a low temperature (0° C. or lower). The resulting crystal is filtered to give Form B (Yield 90%). Thus prepared Crystalline Form B of Lansoprazole is added to acetone, refluxed, filtered, cooled to room temperature, slowly cooled to a lower temperature, and allowed to stand at 0° C. for 3 hours. The resulting crystal is filtered, and dried at a temperature of 50° C. or lower to give Form A (Yield 95%, Yield of the two steps 86%). However, this method has several problems that two steps of preparing Form B and converting Form B to Form A are required, thereby decreasing the total yield; the process should be repeated twice for conversion of the crystalline form; and the whole process requires a long time.
[The Third Process]
This method reported in KR 0433735 obtains Form A by vigorously stirring the Crystalline Form B of Lansoprazole in a solvent mixture of acetone and hexane for 1 hour, filtering the reaction mixture, and drying it for 2 hours. However, this method uses toxic hexane, and so is not appropriate to use industrially. Also, there is a risk that hexane may remain in the product.
The final step for preparing Lansoprazole is typically the oxidation of thio group (S) to sulfinyl group [S(═O)], during which ethanol is usually used as solvent [see EP 0 174 726 (Pyridine derivatives and their production)]. However, when ethanol is used as the crystallizing solvent, Form B is conventionally produced (see PCT/PL00/00042), and so it is expected that Lansoprazole prepared by using ethanol as solvent in the oxidation step is Form B. Thus, there has been a need to develop a process for preparing the Crystalline Form A of Lansoprazole directly from ethanol which is the solvent for preparing Lansoprazole by the oxidation of 2-([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl)thio-1H-benzimidazole.